This proposal for a Chronic Fatigue Syndrome Cooperative Research Center (CFS-CRC) will pursue an integrated, multi-faceted research program that capitalizes on a large well-organized data base already collected and will address a number of practical and theoretical issues in the clinical assessment etiology. and pathogenesis of chronic fatigue syndrome (CFS). Basic science and clinical research are incorporated to develop an interdisciplinary research program of scientific and programmatic importance for CFS patients, clinicians, and researchers. These investigations reflect our central theme: the immunological virological. and psychosocial characterization of CFS and the development of practical, clinically relevant approaches to the evaluation of patients with CFS using an approach that targets specific phases of the illness. In our model of "the four Ps", CFS may occur in a vulnerable individual in whom atopy, psychiatric disorders, female gender. or other genetic, environmental, or cultural predisposing factors are present. Subsequently, a viral infection, accident, or other acute or chronic stressor "triggers" or precipitates illness. Although in most persons, the initial viral infection or other "trigger" is contained and resolves spontaneously, in some the acute condition becomes chronic. During this transition period (typically within the first 6 months of illness), predictors of chronicity become apparent, such as the development of immune and/or neuroendocrine dysfunctions that themselves may lead to additional symptoms. Symptoms then lead to disability, which is both due to, and results in, psychological distress, social dysfunction, stress, and other factors, that perpetuate illness. Thus, with this model in mind, the objectives of this CFS-CRC are to: 1) use monozygotic twins discordant for CFS and subjects with post-infectious fatigue following documented mononucleosis to identify the predisposing factors, precipitants, predictors and perpetuators of chronicity in patients with CFS and post-infectious fatigue; 2) characterize CFS in terms of clinical, functional status, psychiatric and neuropsychological dysfunction, sleep impairment, and other parameters; 3) characterize CFS immunologically using monozygotic twins discordant for CFS, and to utilize basic science techniques in a theoretically guided fashion, to search for a novel infectious agent in individuals at "high risk" for infection based on clinical and laboratory data; 4) compare the symptoms and clinical features of CFS to a syndrome of post-infectious fatigue following documented acute infectious mononucleosis; 5) develop and evaluate the operating characteristics (e.g., sensitivity and specificity) of measures for assessing immunological, neurocognitive, and psychosocial dysfunction in CFS; and 6) use longitudinal follow-up studies to clarify the natural history, prognosis, and predictors of improvement of CFS and post-infectious fatigue. These goals will be accomplished through five individual Research Projects and Administrative, Clinical and Biostatistical and Data Management Cores.